In Hecatomb, each player is an Endbringer, an evil genius bent on the destruction of the modern-day world. Endbringers summon monsters from myth and nightmare, breeding hybrids that can destroy an enemy's forces, eventually building up enough power to destroy the world. After a world is destroyed, the Endbringers travel through dimensional portals to other, parallel worlds where the contest begins again.

Hecatomb's unusual stacking mechanic gives the game a three-dimensional feel. Five-sided Hecatomb cards depict a variety of horrid creatures, from terrible beasts and demons to crazed shamans. Cards feature four clear edges, with scores for power and abilities on the fifth edge. Players can create frightening creature hybrids called Abominations by stacking cards on top of each other. Each Abomination combines the powers and special abilities of all the creatures used to assemble it. The clear edges allow players to see the total power scores and abilities of up to 5 cards stacked together.